Chronic low dose inorganic arsenic (iAs) exposure leads to changes in gene expression and epithelial-to-mesenchymal transformation. During this transformation, cells adopt a fibroblast-like phenotype accompanied by profound gene expression changes. While many mechanisms have been implicated in this transformation, studies that focus on the role of epigenetic alterations in this process are just emerging. DNA methylation controls gene expression in physiologic and pathologic states. Several studies show alterations in DNA methylation patterns in iAs-mediated pathogenesis, but these studies focused on single genes. We present a comprehensive genome-wide DNA methylation analysis using methyl-sequencing to measure changes between normal and iAs-transformed cells. Additionally, these differential methylation changes correlated positively with changes in gene expression and alternative splicing. Interestingly, most of these differentially methylated genes function in cell adhesion and communication pathways. To gain insight into how genomic DNA methylation patterns are regulated during iAs-mediated carcinogenesis, we show that iAs probably targets CTCF binding at the promoter of DNA methyltransferases, regulating their expression. These findings reveal how CTCF binding regulates DNA methyltransferase to reprogram the methylome in response to an environmental toxin.
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This work was supported by NSF grant MCB 1517986 to YFN-M, NIEHS grant R01-ES024478 to YNF-M and NIH T32 grant 165990 to MR, through Markey Cancer Center at University of Kentucky.
The datasets generated during and/or analyzed during the current study are available in the NIH GEO repository; GEO accession numbers for Methyl-MiniSeq data are GSE85012 and Affymetrix Array accession number is GSE90811.
Supplementary information accompanies this paper at http://www.nature.com/srep
Rea, Matthew; Eckstein, Meredith; Eleazer, Rebekah; Smith, Caroline; and Fondufe-Mittendorf, Yvonne N., "Genome-Wide DNA Methylation Reprogramming in Response to Inorganic Arsenic Links Inhibition of CTCF Binding, DNMT Expression and Cellular Transformation" (2017). Molecular and Cellular Biochemistry Faculty Publications. 114.